Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an endogenous 30-amino acid gut peptide, which binds at the GLP-1 receptor coupled to the cyclic AMP second messenger pathway. GLP-1 receptor stimulation enhances pancreatic islet beta-cell proliferation, glucose-dependent insulin secretion and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. Not limited to the pancreas, the chemoarchitecture of GLP-1 receptor distribution in the brain of rodents and humans correlates with a central role for GLP-1 in the regulation of food intake. However emerging evidence suggests that stimulation of neuronal GLP-1 receptors plays an important role in regulating neuronal plasticity and cell survival. GLP-1 has been documented to induce neurite outgrowth and to protect against excitotoxic cell death and oxidative injury in cultured neuronal cells. Moreover, GLP-1 and exendin-4, a naturally occurring more stable analogue of GLP-1 that likewise binds at the GLP-1 receptor, were shown to reduce endogenous levels of amyloid-beta peptide (Abeta) in mouse brain and to reduce levels of beta-amyloid precursor protein (betaAPP) in neurons. Collectively these data suggest that treatment with GLP-1 or a related peptide beneficially affects a number of the therapeutic targets associated with Alzheimer's disease (AD). Although much remains to be elucidated with regards to the downstream signaling pathways involved in the pro-survival properties of GLP-1, modulation of calcium homeostasis may be critical. This review will consider the potential therapeutic relevance of GLP-1 to CNS disorders, such as AD.
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PMID:A new Alzheimer's disease interventive strategy: GLP-1. 1527 Feb 3

The available evidence suggests that about two-thirds of the insulin response to an oral glucose load is due to the potentiating effect of gut-derived incretin hormones. The strongest candidates for the incretin effect are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). In patients with type 2 diabetes, however, the incretin effect is lost or greatly impaired. It is hypothesized that this loss explains an important part of the impaired insulin secretion in patients. Further analysis of the incretin effects in patients has revealed that the secretion of GIP is near normal, whereas the secretion of GLP-1 is decreased. On the other hand, the insulintropic effect of GLP-1 is preserved, whereas the effect of GIP is greatly reduced, mainly because of a complete loss of the normal GIP-induced potentiation of second-phase insulin secretion. These two features, therefore, explain the incretin defect of type 2 diabetes. Strong support for the hypothesis that the defect plays an important role in the insulin deficiency of patients is provided by the finding that administration of excess GLP-1 to patients may completely restore the glucose-induced insulin secretion as well as the beta-cells' sensitivity to glucose. Because of this, analogs of GLP-1 or GLP-1 receptor activations are currently being developed for diabetes treatment, so far with very promising results.
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PMID:Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. 1527 45

To address the possibility that the partial disruption of Glucagon-like peptide-1 (GLP-1) signaling could cause diabetes, we tried to detect the mutation in GLP-1 receptor (GLP-1R) gene in the population with type 2 diabetes. Genomic DNA was extracted from 36 unrelated Japanese type 2 diabetic subjects and directly sequenced for the GLP-1R gene. For the detected polymorphisms, 791 patients with type 2 diabetes and 318 controls were screened by polymerase chain reaction-restricted fragment length polymorphism and association study was carried out. Five missense and four silent variants were detected in the GLP-1R gene. There were no significant differences in the frequencies of Pro7Leu, Arg44His and Leu260Pro polymorphism between the diabetic and control groups. And also there were no significant differences in body mass index (BMI), onset age and fasting IRI among the wild type, heterozygote and homozygote of these variants in diabetic patients. Thr149Met mutation was detected in one case among 791 type 2 diabetes patients, but not in control subjects. The patient with this mutation exhibited impairment of both insulin secretion, insulin sensitivity and glucose effectiveness, which may be partially explained by Thr149Met mutation in GLP-1R, though family linkage analysis and function analysis remain to be examined.
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PMID:Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population. 1536 63

Glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin secretion and inhibits food intake, gastric emptying, and glucagon secretion, actions that promote reduction of fasting and postprandial glycemia in subjects with type 2 diabetes. The rapid degradation of native GLP-1 has engendered interest in more stable longer-acting GLP-1 receptor agonists such as exendin-4 (Ex-4); however, the potential consequences of sustained GLP-1 receptor activation leading to receptor desensitization has not been extensively studied. We have now examined a range of GLP-1 receptor-dependent responses following treatment with Ex-4 using INS-1 cells in vitro and both wild-type control and MT-Ex-4 transgenic mice in vivo. Although both GLP-1 and Ex-4 acutely desensitized GLP-1 receptor-dependent cAMP accumulation in INS-1 cells, Ex-4 produced more sustained receptor desensitization, relative to GLP-1, in both acute (5-120 min) and chronic (24-72 h) experiments. PMA (4-phorbol 12-myristate 13-acetate) but not glucagon, glucose-dependent insulinotropic polypeptide (GIP), or epinephrine produced heterologous desensitization in vitro. MT-Ex-4 transgenic mice exhibited a reduced glycemic response to oral but not intraperitoneal glucose challenge following acute Ex-4 administration. In contrast, no differences in glycemic excursion or plasma insulin were observed after 1 week of twice-daily Ex-4 administration to wild-type versus MT-Ex-4 mice. Similarly, the levels of insulin, pdx-1, and GLP-1 receptor mRNA transcripts were comparable in wild-type and MT-Ex-4 transgenic mice after 1 week of Ex-4 administration. However, repeated Ex-4 administration significantly reduced food intake in MT-Ex-4 but not in wild-type mice. These findings illustrate that although Ex-4 is more potent than native GLP-1 in producing GLP-1 receptor desensitization in vitro, chronic exposure to Ex-4 in normal or transgenic mice is not associated with significant downregulation of GLP-1 receptor-dependent responses coupled to glucose homeostasis in vivo.
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PMID:Chronic exposure to GLP-1R agonists promotes homologous GLP-1 receptor desensitization in vitro but does not attenuate GLP-1R-dependent glucose homeostasis in vivo. 1556 12

A lot of interest has engendered in glucagon-like peptide-1 (GLP-1) as an emerging new drug in the treatment of type 2 diabetes. GLP-1 exerts several effects that reduce glycemia in type 2 diabetes patients. We recently also demonstrated that GLP-1 ameliorates endothelial dysfunction in type 2 diabetes mellitus patients with established coronary heart disease, suggesting a new important cardioprotective role for GLP-1. Because hypertension is overrepresented in diabetes and is adversely influencing survival, we have now investigated direct GLP-1 effects on vascular beds in a rat organ bath model. It was found that GLP-1 relaxed femoral artery rings in a dose-response manner. The relaxant effect from GLP-1 was completely inhibited by the specific GLP-1 receptor antagonist, exendin(9-39). Neither the specific nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine, nor removing of endothelium, affected the GLP-1 relaxant effect. In conclusion, we now report a direct vascular action of GLP-1, relaxing conduit vessels independently of NO and the endothelium.
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PMID:Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism. 1558 29

Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently being explored as a new approach to the treatment of type 2 diabetes. This concept has emerged from the powerful and rapid action of the enzyme to inactivate glucagon-like peptide-1 (GLP-1). However, other bioactive peptides with potential influence of islet function are also substrates of DPP-4. Whether this inactivation may add to the beneficial effects of DPP-4 inhibition is not known. In this study, we explored whether DPP-4 inhibition by valine-pyrrolidide (val-pyr; 100 micromol/kg administered through gastric gavage at t = -30 min) affects the insulin and glucose responses to iv glucose (1 g/kg) together with GLP-1 (10 nmol/kg), glucose-dependent insulinotropic polypeptide (GIP; 10 nmol/kg), pituitary adenylate cyclase-activating polypeptide 38 (PACAP38; 1.3 nmol/kg), or gastrin-releasing peptide (GRP; 20 nmol/kg) given at t = 0 in anesthetized C57BL/6J mice. It was found that the acute (1-5 min) insulin response to GLP-1 was augmented by val-pyr by 80% (4.2 +/- 0.4 vs. 7.6 +/- 0.8 nmol/liter), that to GIP by 40% (2.7 +/- 0.3 vs. 3.8 +/- 0.4 nmol/liter), that to PACAP38 by 75% (4.6 +/- 0.5 vs. 8.1 +/- 0.6 nmol/liter), and that to GRP by 25% (1.8 +/- 0.2 vs. 2.3 +/- 0.3 nmol/liter; all P < 0.05 or less). This was associated with enhanced glucose elimination rate after GLP-1 [glucose elimination constant (K(G)) 2.1 +/- 0.2 vs. 3.1 +/- 0.3%/min] and PACAP38 (2.1 +/- 0.3 vs. 3.2 +/- 0.3%/min; both P < 0.01), but not after GIP or GRP. The augmented insulin response to GRP by val-pyr was prevented by the GLP-1 receptor antagonist, exendin(3) (9-39), raising the possibility that GRP effects may occur secondary to stimulation of GLP-1 secretion. We conclude that DPP-4 inhibition augments the insulin response not only to GLP-1 but also to GIP, PACAP38, and GRP.
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PMID:Inhibition of dipeptidyl peptidase-4 augments insulin secretion in response to exogenously administered glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, pituitary adenylate cyclase-activating polypeptide, and gastrin-releasing peptide in mice. 1560 13

Glucagon-like peptide 1 (GLP-1), a gut incretin hormone that stimulates insulin secretion, also activates antiapoptotic signaling pathways such as phosphoinositide 3-kinase and mitogen-activated protein kinase in pancreatic and insulinoma cells. Since these kinases have been shown to protect against myocardial injury, we hypothesized that GLP-1 could directly protect the heart against such injury via these prosurvival signaling pathways. Both isolated perfused rat heart and whole animal models of ischemia/reperfusion were used, with infarct size measured as the end point of injury. In both studies, GLP-1 added before ischemia demonstrated a significant reduction in infarction compared with the valine pyrrolidide (an inhibitor of its breakdown) or saline groups. This protection was abolished in the in vitro hearts by the GLP-1 receptor antagonist exendin (9-39), the cAMP inhibitor Rp-cAMP, the PI3kinase inhibitor LY294002, and the p42/44 mitogen-activated protein kinase inhibitor UO126. Western blot analysis demonstrated the phosphorylation of the proapoptotic peptide BAD in the GLP-1-treated groups. We show for the first time that GLP-1 protects against myocardial infarction in the isolated and intact rat heart. This protection appears to involve activating multiple prosurvival kinases. This finding may represent a new therapeutic potential for this class of drug currently undergoing clinical trials in the treatment of type 2 diabetes.
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PMID:Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. 1561 22

Type 2 diabetes is a polygenic disorder characterized by increased insulin resistance, and impaired insulin secretion leading to abnormalities of glucose and lipid metabolism. Reduced responsiveness of the beta-cells to glucose is a critical feature of this syndrome. Glucagon-like peptide 1, a product of the pro-glucagon gene makes beta-cells competent and has many other anti-diabetic properties. We speculated whether GLP-1-based gene therapy could be an approach for treatment of type 2 diabetes. We started with a clone of rat insulinoma cells (S4 cells), which showed reduced responsiveness to glucose in terms of insulin secretion. We transfected these cells with a plasmid encoding a mutated form of GLP-1 (GLP-1-Gly8), which is resistant to the degrading enzyme dipeptidyl-peptidase IV. Activity of secreted GLP-1-Gly8 was assayed using Chinese hamster lung fibroblasts (CHL) cells that expressed cloned GLP-1 receptor and that were transfected with CRE-Luc. Stable cell lines (Glipsulin cells) obtained by this means produced and stored immunoreactive GLP-1-Gly8. In addition to insulin, the Glipsulin cells secreted the GLP-1-Gly8. The secreted GLP-1-Gly8 was active as evidenced by the ability of the conditioned media to elevate cAMP levels in CHL cells expressing GLP-1 receptors. Glipsulin cells responded to glucose with a 6.8 fold increase in insulin secretion compared to a 2.2 fold increase in the control cells. Our results demonstrate that prolonged exposure to GLP-1-Gly8 secreted by increases glucose-responsiveness of these cells. We speculate that engineering GLP-1-Gly8 secretion by beta-cells is a potential gene therapeutic strategy to treat diabetes.
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PMID:Engineered beta-cells secreting dipeptidyl peptidase IV-resistant glucagon-like peptide-1 show enhanced glucose-responsiveness. 1564 94

Over the last decade, remarkable strides in incretin hormone biology have laid the foundation for our more recent appreciation that GLP-1 not only regulates mature beta-cell function but also critically regulates beta-cell differentiation, beta-cell proliferation and beta-cell survival. Dysregulated beta-cell growth and function are central to the pathophysiology of both type 1 and type 2 diabetes. Thus, GLP-1 receptor agonists are being intensively developed for the treatment of human diabetes and are likely to become available to clinical use in the near future. A general overview of beta-cell development will be provided, with particular emphasis on recent contributions to our understanding of pancreas and islet development during the embryonic, fetal and neonatal periods. The transcriptional hierarchy and extracellular signals governing events during these periods will be highlighted. Evidence suggesting a role for endogenous GLP-1 and GLP-1 receptor during beta-cell development will be reviewed. Finally, the therapeutic potential for intervention with GLP1 receptor agonists during the neonatal period will be discussed.
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PMID:The development of beta-cell mass: recent progress and potential role of GLP-1. 1565 13

Glucagon-like peptide-1 (GLP-1) is an incretin hormone with antidiabetic action through its ability to stimulate insulin secretion, increase beta cell neogenesis, inhibit beta cell apoptosis, inhibit glucagon secretion, delay gastric emptying and induce satiety. It has therefore been explored as a novel treatment of type 2 diabetes. A problem is, however, that GLP-1 is rapidly inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme, which results in a short circulating half-life of the active form of GLP-1 (< 2 min). Two strategies have been employed to overcome this obstacle as a treatment of diabetes. One is to use GLP-1 receptor agonists that have a prolonged half-life due to reduced degradation by DPP-4. These GLP-1 mimetics include exenatide and liraglutide. Another strategy is to inhibit the enzyme DPP-4, which prolongs the half-life of endogenously released active GLP-1. Both these strategies have been successful in animal studies and in clinical studies of up to one year's treatment. This review will summarize the background and the current (mid 2004) clinical experience with these two strategies.
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PMID:GLP-1 receptor agonists and DPP-4 inhibitors in the treatment of type 2 diabetes. 1565 21


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